The "graft-versus-leukemia" effect of allogeneic blood or marrow transplantation (alIoBMT) is perhaps the best evidence that T cells can mediate the destruction of disseminated human malignancies. Unfortunately, alloBMT is quite toxic, especially when the transplant is performed after high-dose, myeloablative conditioning of the recipient, and there is no conclusive evidence that alIoBMT is effective in the treatment of common solid tumors. Using a nonmyeloablative allogeneic stem cell transplantation (NST) protocol that induces stable mixed hematopoietic chimerism, we have induced potent therapeutic anti-tumor immunity in a mouse model of metastatic breast cancer by administering post-transplantation donor lymphocyte infusions (DLI) and a GM-CSF-based autologous tumor cell vaccine. In this model, the host immune system is an essential participant in the curative response to immunotherapy. Our central hypothesis is that well established tumors do not induce irreversible tolerance in endogenous tumor-specific CD8+ T cells, which may be induced to effector function by vaccination in the context of a concomitant "allogeneic effect" mediated by donor CD4+ T cell responses to histocompatibility antigens. A prediction of this model is that a similar anti-tumor effect can be achieved after non-myeloablative conditioning and autologous BMT, so long as concomitant CD4+ T cell help is provided. There are two specific aims of this proposal. In the first aim, we will use mouse tumors expressing influenza hemagglutinin (HA) and transgenic, HA-specific CD4+ and/or CD8+ T cells to characterize the novel cooperation of host and allogeneic donor T cells in the response of transient or stable mixed hematopoietic chimeras to tumor cell vaccines. In the second aim, we will test a strategy of providing CD4+ T cell help for tumor vaccine responses by expressing defined CD4+ T cell epitopes in antigen-presenting cells via lentiviral transduction of transplanted autologous hematopoietic stem cells.